Saying NO to Sickle-Cell Pain

Nitric oxide (NO), the 1998 Nobel Prize-winning wonder gas, plays a central role in just about every physiological process in the human body. One of its functions is to dilate blood vessels in order to regulate blood pressure. Now, a new study shows that NO's cardiovascular role holds the key to the long-mysterious pain associated with sickle-cell anemia, along with a possible antidote.

People with sickle-cell anemia have a genetic mutation that causes hemoglobin to crystallize inside their red blood cells. The sharp hemoglobin molecules weaken the membranes, causing the cells to rupture. Up to 10% of all red blood cells can burst in a single day, dumping hemoglobin into the blood stream. This somehow constricts the blood vessels and causes intense pain. Until now, however, the chain of events wasn't known.

NO is the missing link, says senior author Mark Gladwin, a pulmonologist at the National Institutes of Health's Clinical Center in Bethesda, Maryland. When hemoglobin hits the bloodstream, it has been found to gobble up the NO released by vessels 1000 times faster than from inside the red blood cell. Gladwin's group found that patients with sickle-cell disease indeed had higher rates of NO consumption. But their blood's appetite for NO fell to near normal when the unpackaged hemoglobin was removed from samples in the lab, the team reports in the 11 November online edition of Nature Medicine.

An even more intriguing result came from sickle-cell patients who were asked to inhale NO gas. This converted the NO-guzzling hemoglobin in their blood to two forms of hemoglobin that do not consume NO as rapidly. This inhalation therapy allowed NO to carry on with its usual job of regulating vessel diameter. Although patients in this study were not in the midst of a pain crisis, authors are optimistic that NO-inhalation therapy would work to alleviate pain in such cases.

The study is "elegant and compelling," says physiologist Jack Lancaster of the University of Alabama, Birmingham (UAB). Making more NO more available to the tissue--through NO-inhalation therapy, for example--could be "beneficial for the treatment of sickle cell disease," agrees UAB biochemist Mutay Aslan.